Going Round in Circles with N→S Acyl Transfer

Macmillan, Derek

doi:10.1055/s-0036-1588789

Cited by 8 publications

(2 citation statements)

References 73 publications

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“…However, this conversion requires harsh heating conditions, which may not be compatible with some peptides. In contrast, Gly-Cys is a favorable motif for thioesterification employing the N-to-S acyl shift at Cys . This allowed us to prepare peptide-CGt from peptide-CGC under milder reaction conditions, providing a robust method that inspired by the sophisticated CPE method.…”

Section: Resultsmentioning

confidence: 99%

Semisynthesis of a Homogeneous Glycoprotein Using Chemical Transformation of Peptides to Thioester Surrogates

et al. 2021

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Semisynthesis using recombinant polypeptides as building blocks is a powerful approach for the preparation of proteins with a variety of modifications such as glycosylation. The activation of the C terminus of recombinant peptides is a key step for coupling peptide building blocks and preparing a full-length polypeptide of a target protein. This article reports two chemical approaches for transformation of the C terminus of recombinant polypeptides to thioester surrogates. The first approach relies on efficient substitution of the C-terminal Cys residue with bis(2-sulfanylethyl)amine (SEA) to yield peptide-thioester surrogates. The second approach employs a native tripeptide, cysteinyl-glycyl-cysteine (CGC), to yield peptide-thioesters via a process mediated by a thioester surrogate. Both chemical transformation methods employ native peptide sequences and were thereby successfully applied to recombinant polypeptides. As a consequence, we succeeded in the semisynthesis of a glycosylated form of inducible T cell costimulator (ICOS) for the first time.

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Section: Resultsmentioning

confidence: 99%

Semisynthesis of a Homogeneous Glycoprotein Using Chemical Transformation of Peptides to Thioester Surrogates

et al. 2021

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“… 17 These acyl transfer auxiliaries consist of a tertiary amide to aid distortion of the amide bond (ground-state destabilization), and a pendant thiol to enable an intramolecular proximity-driven N -to- S acyl transfer ( Figure S1 ). 18 The N -to- S acyl transfer reaction is typically reversible and, therefore, the transient thioester is either used in situ in a ligation reaction, or transthioesterified with excess thiol to form a stable C -terminal peptide thioester. 19 …”

Section: Introductionmentioning

confidence: 99%

N-to-S Acyl Transfer as an Enabling Strategy in Asymmetric and Chemoenzymatic Synthesis

Jo,

Curtis,

Rehan

et al. 2024

JACS Au

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The observation of thioester-mediated acyl transfer processes in nature has inspired the development of novel protein synthesis and functionalization methodologies. The chemoselective transfer of an acyl group from S-to-N is the basis of several powerful ligation strategies. In this work, we sought to apply the reverse process, the transfer of an acyl group from N-to-S, as a method to convert stable chiral amides into more reactive thioesters. To this end, we developed a novel cysteine-derived oxazolidinone that serves as both a chiral imide auxiliary and an acyl transfer agent. This auxiliary combines the desirable features of rigid chiral imides as templates for asymmetric transformations with the synthetic applicability of thioesters. We demonstrate that the auxiliary can be applied in a range of highly selective asymmetric transformations. Subsequent intramolecular N-to-S acyl transfer of the chiral product and in situ trapping of the resulting thioester provides access to diverse carboxylic acid derivatives under mild conditions. The oxazolidinone thioester products can also be isolated and used in Pd-mediated transformations to furnish highly valuable chiral scaffolds, such as noncanonical amino acids, cyclic ketones, tetrahydropyrones, and dihydroquinolinones. Finally, we demonstrate that the oxazolidinone thioesters can also serve as a surrogate for SNAC-thioesters, enabling their seamless use as non-native substrates in biocatalytic transformations.

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Amide‐Forming Ligation Reactions

2019

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One of the long‐standing pursuits of synthetic organic chemists is the development of chemical methods for the synthesis of peptides and proteins as tools for understanding biological processes and providing therapeutic solutions to human diseases. The advent of chemoselective ligation reactions for the chemical synthesis of peptides and proteins has enabled synthetic chemists to realize this long‐held dream. In an amide‐forming ligation reaction, two uniquely placed functional groups within the peptide allow peptide or protein segments to be joined in a chemoselective manner with an amide bond. In this chapter, some of the early methods based on principles of the capture/rearrangement strategy for ligation of peptides are catalogued, followed by some of the most versatile and well‐established contemporary methods for the preparation of linear/cyclic peptides and proteins such as the native chemical ligation (NCL) and the α‐ketoacid–hydroxylamine (KAHA) ligation. The chapter concludes with some of the most promising new generation ligation methods such as the potassium acyltrifluoroborate–hydroxylamine (KAT) ligation. The tremendous progress in the past two decades in the development of several ligation methods that rely on a pair of unique functional groups is set to expand the horizons of fully functional proteins and multi‐protein assemblies that are purely synthetically prepared. Although contemporary ligation reactions do not match the speed and efficiency at which proteins are assembled in biological systems, the repertoire of chemoselective amide‐forming ligation methods has already enabled synthetic protein chemistry to surpass biology in terms of chemical and structural diversity.

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Going Round in Circles with N→S Acyl Transfer

Cited by 8 publications

References 73 publications

Semisynthesis of a Homogeneous Glycoprotein Using Chemical Transformation of Peptides to Thioester Surrogates

Semisynthesis of a Homogeneous Glycoprotein Using Chemical Transformation of Peptides to Thioester Surrogates

N-to-S Acyl Transfer as an Enabling Strategy in Asymmetric and Chemoenzymatic Synthesis

Amide‐Forming Ligation Reactions

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